A novel link between Slc22a18 and fat accumulation revealed by a mutation in the spontaneously hypertensive rat
A novel link between Slc22a18 and fat accumulation revealed by a mutation in the spontaneously hypertensive rat
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DOI：
10.1016/j.bbrc.2013.09.096
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发表时间：
2013-11-01
影响因子：
3.1
通讯作者：
Gotoda, Takanari
中科院分区：
文献类型：
--
作者：
Yamamoto, Takashi;Izumi-Yamamoto, Kozue;Gotoda, Takanari
存在两种不同品系的自发性高血压大鼠（SHR），一种有Cd36突变，一种没有。在由这两种SHR品系杂交产生的F2群体中，突变的Cd36等位基因与代谢表型的差异紧密相关，但与脂肪垫重量无关。这表明存在另一个与肥胖相关的关键突变。对该F2群体的连锁分析显示，大鼠1号染色体区域（D1Rat240 - D1Wox28）与脂肪垫重量之间存在显著连锁。通过整合定位和表达信息，我们在脂肪垫重量降低的SHR中发现溶质载体家族22成员18（Slc22a18）基因的一个供体剪接位点突变。该突变位于连锁峰值处，最大优势对数评分值为7.7，导致整个第9外显子缺失，从而使大鼠Slc22a18蛋白的一个完整跨膜区域完全缺失。Slc22a18 mRNA在分离的脂肪细胞中大量表达，并且在3T3 - L1细胞中呈分化依赖方式表达。通过腺病毒载体感染降低Slc22a18 mRNA的表达，显著抑制了3T3 - L1细胞中甘油三酯的积累和脂肪细胞的分化。相反，Slc22a18 mRNA的过表达具有相反的效果。这些结果揭示了Slc22a18与脂肪积累之间的一种新联系，并表明该基因可能是肥胖症的一个新治疗靶点。（C）2013爱思唯尔公司。保留所有权利。
Two different strains of the spontaneously hypertensive rat (SHR) exist, either with or without a Cd36 mutation. In the F2 population derived from a cross between these two SHR strains, the mutant Cd36 allele was tightly linked to differences in metabolic phenotypes but not to those in fat pad weight. This suggested the existence of another crucial mutation related to adiposity. Linkage analysis of this F2 population showed a significant linkage between the rat chromosome 1 region (D1Rat240-D1Wox28) and fat pad weight. By integrating both positional and expression information, we identified a donor splice site mutation in the gene for solute carrier family 22 member 18 (Slc22a18) in SHR with reduced fat pad weight. This mutation was located at the linkage peak with a maximum logarithm of odds score of 7.7 and caused skipping of the whole exon 9 that results in a complete loss of a whole membrane-spanning region of the rat Slc22a18 protein. Slc22a18 mRNA was abundantly expressed in isolated adipocytes and in a differentiation-dependent manner in 3T3-L1 cells. Knockdown of the Slc22a18 mRNA via infection of adenoviral vectors markedly inhibited both triglyceride accumulation and adipocyte differentiation in 3T3-L1 cells. By contrast, overexpression of the Slc22a18 mRNA had the opposite effects. These results reveal a novel link between Slc22a18 and fat accumulation and suggest that this gene could be a new therapeutic target in obesity. (C) 2013 Elsevier Inc. All rights reserved.